It is somewhat paradoxical that NF-L abundance is increased in peripheral biofluids in multiple forms of neurodegeneration while being significantly downregulated within CNS neurons, however molecular-genetic mechanisms involving altered NF-L trafficking in AD and other neurodegenerative diseases and the utilization of cellular exosomes (EXs), extracellular microvesicles (EMVs) and other altered translocation mechanisms for NF-L have recently been proposed to clarify this perplexing observation (18, 20–23). This evidence concerns the gene NEFL and Alzheimer disease.